Benzosuberonylpiperdine compounds as analgesics

ABSTRACT

Compounds of formula (I) or a derivative thereof, wherein; R is C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 alkoxy, hydroxy, halo, C 1-6 alkenyl, C 1-6 alkynyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, hydroxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, aminoC 1-6 alkyl, (C 1-6 alkyl)aminoC 1-6 alkyl, di(C 1-6 alkyl)aminoC 1-6 alkyl; R 1  is hydrogen or R; R 2  is hydroxy, C 1-6 alkoxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino; R 3  is hydrogen or C 1-6 alkyl; R 4  and R 5  are each independently selected from the list consisting of perhaloC 1-6 alkyl, hydrogen, halo, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, hydroxyC 1-6 alkyl, C 1-6 alkoxyC 1-6 alkyl, aminoC 1-6 alkyl, (C 1-6 alkyl)aminoC 1-6 alkyl, di(C 1-6 alkyl)aminoC 1-6 alkyl, aryl, and COX wherein X may be hydroxy, C 1-6 alkoxy, C 1-6 alkyl, amino, C 1-6 alkylamino, or di(C 1-6 alkyl)amino; with the proviso that, when R 3  is hydrogen, then R 4  and R 5  are not both hydrogen; and wherein any alkyl group or the alkyl moiety of any group containing such a moiety may be substituted one or more times by halo; are ligands of the ORL-1 receptor and are useful in therapy.

The present invention relates to certain novel compounds, to processesfor preparing such compounds, to pharmaceutical compositions containingsuch compounds, and to the use of such compounds in medicine.

The ORL-1 receptor is found throughout the whole of the neuraxis and isknown to be involved in the transmission of pain.

Eur. J. Med. Chem. 1978; 13:533–547 (Eirin et al.) discloses(±)-3-[(4-phenylpiperidin-1-yl)methyl]-1-oxo-2H-3,4-diydronaphthalenefor use as a neuroleptic agent An. Real. Acad. Farm. 1989;55:461–469(Santana et al.) discloses(±)-2-[(4-phenylpiperidin-1-yl)methyl]-1,2,3,4-tetrahydronaphthalene asan antidopaminergic agent. U.S. Pat. No. 4,022,791 (Pfizer Inc.)discloses certain 2-aminomethyl-3,4-dihydronaphthalenes as analgesics.J. Med. Chem. 1977;20(5):699–705 (Welch et al) discloses5,8-disubstituted 1-tetralones as analgesics and tranquillisers. J. Med.Chem. 1978;21(3):257–263 (Welch et al) discloses certain5,8-disubstituted 2-aminomethyl-3,4-dihydronaphthalenes as analgesicsand tranquillisers. International Application Publication Number WO98/36749 (Bristol-Myers Squibb) discloses certain tetralone derivativesas antiarrhythmic agents. United Kingdom Patent Application GB 2177085(Imperial Chemical Industries PLC) discloses certainbenzocycloalkylmethylamines as fungicides. WO 99/06397 (AbbottLaboratories) discloses certain piperidine compounds useful asendothelin antagonists. WO 98/02432 (Takeda Chemical Industries Ltd)discloses certain phenylpiperidino compounds useful for the treatment oflower urinary tract infections. WO 96/22977 (Suntory Limited) disclosescertain piperidinyl derivatives for treating symptoms of ischaemicdiseases and preventing cytotoxic calcium overload. WO 97/23458(Cocensys Inc.) discloses certain tetrahydronaphthyl and piperidinederivatives as sub-type selective N-methyl-D-aspartame receptor ligands.U.S. Pat. No. 5,436,255 Pfizer Inc.) discloses certain3-piperidino-1-chromanof derivatives for blocking the NMDA receptorsite. WO 95/00131 (University of Virginia Commonwealth) disclosescertain amine derivatives as useful in the treatment of CNS disorders.European Patent Application EP 0 745 598 (Adir et Compagnie) disclosescertain piperazine, piperidine, and tetrahydropyridine compounds asligands of the D₄ dopamine receptor. EP 0 742 207 (Eisai Co. Ltd.)discloses certain cyclic amines as having acetyleholine esteraseactivity. U.S. Pat. No. 5,215,989 (Merck & Co. Inc.) discloses certaindisubstituted piperazine and imidazole derivatives useful as Class IIIantiarrhythmic agents. WO 93/00313 (University of Virginia Commonwealth)discloses certain amine derivatives as selective sigma receptor bindingagents. EP 0 479 601 (Ajinomoto K K) discloses certain piperidinederivatives as antiarrhythmic agents. Japanese Patent Application JP2169 569 (Eisai K K) discloses certain cyclic amine derivatives for thetreatment or prophylaxis of e.g. senile dementia, cerebral apoplexy, andcerebral atherosclerosis. WO 00/06545 (Schering Corporation) disclosescertain piperidine and tetrahydropyridine derivatives as ORL-1 receptorligands. WO 00/14067 (F. Hofmann-La Roche AG) discloses certainpiperidine derivatives as ligands for the OFQ (ORL-1) receptor. WO98/51687 (Fujisawa Pharmaceutical Co.) discloses certain piperidinoderivatives as promoters of growth hormone release. WO 98/33758 (TakedaChemical Industries) discloses certain bicyclic quinone compounds. GB2292558 (Merck and Co.) discloses certain bicyclic compounds asfibrinogen receptor antagonists. WO 00/55137 (Axys Pharmaceuticals)discloses certain bicyclic compounds as modulators of estrogenreceptors. WO 00/32582 (Glaxo Group Limited) discloses benzamidederivatives as APOB-100 secretion inhibitors. WO 00/27815 (SmithKlineBeecham SpA) discloses N-substituted azacycles as ORL-1 inhibitors. WO00/12074 (Scios Inc.) discloses certain piperidines and piperazines asinhibitors of P-38 alpha kinase. WO 98/38156 (Takeda Chemical IndustriesLtd.) discloses certain amino compounds and their use as amyloid-betaproduction inhibitors. EP 846683 (F. Hoffmann La Roche AG) disclosescertain hydroxypiperidine derivatives.

It has now surprisingly been found that certain benzosuberonylpiperidinederivatives are ligands of the ORL-1 receptor, and therefore may beuseful as analgesics in humans or animals for the treatment of, forexample, acute pain; chronic neuropathic or inflammatory pain includingpost herpetic neuralgia; neuralgia; diabetic neuropathy and post strokepain; osteoarthritis/back pain; painful pregnancy labour; and therapy ofopioid tolerance and dependence.

These compounds may also therefore be useful in the treatment orprophylaxis of eating disorders such as anorexia and bulimia; anxietyand stress conditions; immune system diseases; cardiovascular systemdysfunctions; memory loss; cognitive disorders; motor impairment andneurodegeneration owing to Alzheimer's disease; senile dementia;Parkinson's disease or other neurodegenerative pathologies; stroke;epilepsy; altered diuresis and sodium excretion; syndrome ofinappropriate secretion of antidiuretic dormone (SIADH); adultrespiratory distress syndrome (ARDS); congestive heart failure;cirrhosis with ascites; sexual dysfunctions including impotence andfrigidity; and altered pulmonary function, including chronic obstructivepulmonary disease.

These compounds may also therefore be useful in the treatment orprophylaxis of cough; asthma; depression; drug abuse such as alcoholabuse; dementias such as vascular dementia and AIDS dementia complex;metabolic disorders such as obesity; arterial blood pressure disorders;and for the control of water balance and sodium excretion.

Accordingly, the present invention provides a compound of formula (I)

or a derivative thereof,wherein;

R is C₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkoxy, hydroxy, halo, C₁₋₆alkenyl,C₁₋₆alkynyl, amino, C₁₋₆alklylamino, di(C₁₋₆alkyl)amino,hydroxyC₁₋₆alkyl, C₁-6alkoxyC₁₋₆alkyl, aminoC₁₋₆alkyl,(C₁₋₆alkyl)aminoC₁₋₆alkyl, di(C₁₋₆alkyl)aminoC₁₋₆alkyl;

R¹ is hydrogen or R;

R² is hydroxy, C₁₋₆alkoxy, amino, C₁₋₆alkylamino, di(C₁₋₆allyl)amino;

R³ is hydrogen or C₁₋₆alkyl;

R⁴ and R⁵ are each independently selected from the list consisting ofperhaloC₁₋₆alkyl, hydrogen, halo, C₁₋₆alkyl, C₁₋₆alkoxy, hydroxy, amino,C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, hydroxyC₁₋₆alkyl,C₁₋₆alkoxyC₁₋₆alkyl, aminoC₁₋₆alkyl, (C₁₋₆alkyl)aminoC₁₋₆alkyl,di(C₁₋₆alkyl)aminoC₁₋₆alkyl, aryl, and COX wherein X may be hydroxy,C₁₋₆ alkoxy, C₁₋₆alkyl, amino, C₁₋₆alkylamino, or di(C₁₋₆alkyl)amino;with the proviso that, when R³ is hydrogen, then R⁴ and R⁵ are not bothhydrogen; and wherein any alkyl group or the alkyl moiety of any groupcontaining such a moiety may be substituted one or more times by halo.

Suitably, R is C₁₋₆alkenyl, C₁₋₆alkyl, halo, or C₁₋₆alkoxy.

Favourably, R is vinyl, allyl, ethyl, methyl, fluoro, bromo, or methoxy.

Preferably, R is methyl, fluoro, or bromo.

More preferably, R is methyl.

Suitably, R¹ is hydrogen or methyl.

Favourably, R¹ is hydrogen or 4-methyl.

Suitably, R² is hydroxy.

Favourably, R³ is hydrogen or methyl.

Preferably, R³ is hydrogen.

Suitably, R⁴ is hydroxyC₁₋₆alkyl, halo, perhaloC₁₋₆alkyl, C₁₋₆alkyl, orhydrogen.

Favourably, R⁴ is hydroxymethyl, fluoro, trifluoromethyl, chloro,methyl, bromo, or hydrogen.

More favourably, R⁴ is 2-hydroxymethyl, 2-F, 2-CF₃, 2-Cl, 2-Me, 3-Me,2-Br, or hydrogen.

Preferably, R⁴ is 2-Cl, 2-F, 2-Me, or 2-Br.

More preferably, R⁴ is 2-Cl or 2-Me.

Suitably, R⁵ is C₁₋₆alkyl, hydrogen, or halo.

Favourably, R⁵ is methyl, hydrogen, fluoro, or chloro.

More favourably, R⁵ is hydrogen, 6-Me, 3-F, 5-F, 6-F, or 6-Cl.

Preferably, R⁵ is hydrogen, 3-F, 6-Me, 6-F, or 6-Cl.

More preferably, R⁵ is 6-Me, 6-F, or 6-Cl.

Preferred compounds of formula (I) are Examples 1, 3, 4, 6, 8, 11, 14,15, 19, 21, 24, 26, 22, 25, 16, and 18.

Compounds of formula (I) which are more preferred are Examples 26, 22,25, 16, and 18.

Suitable derivatives of the compounds of the invention arepharmaceutically acceptable derivatives.

Suitable derivatives of the compounds of the invention include salts andsolvates.

Suitable pharmaceutically acceptable derivatives includepharmaceutically acceptable salts and pharmaceutically acceptablesolvates.

Suitable pharmaceutically acceptable salts include metal salts, such asfor example aluminium, alkali metal salts such as lithium, sodium orpotassium, alkaline earth metal salts such as calcium or magnesium andammonium or substituted ammonium salts, for example those with loweralkylamines such as triethylamine, hydroxy alkylamines such as2-hydroxyethylamine, bis-(2-hydroxyethyl)amine ortri-(2-hydroxyethyl)amine, cycloalkylamines such as bicyclohexylamine,or with procaine, dibenzylpiperidine, N-benzyl-β-phenethylamine,dehydroabietylamine, N,N′-bisdehydroabietylamine, glucamine,N-methylglucamine or bases of the pyridine type such as pyridine,collidine, quinine or quinoline.

Suitable pharmaceutically acceptable salts also includespharmaceutically acceptable acid addition salts, such as those providedby pharmaceutically acceptable inorganic acids or organic acids.

Suitable pharmaceutically acceptable acid addition salts provided bypharmaceutically acceptable inorganic acids includes the sulphate,nitrate, phosphate, borate, hydrochloride hydrobromide and hydroiodide.

Suitable pharmaceutically acceptable acid addition salts provided bypharmaceutically acceptable organic acids includes the acetate,tartrate, maleate, fulmarate, malonate, citrate, succinate, lactate,oxalate, benzoate, ascorbate, methanesulphonate, α-ketoglutarate andα-glycerophosphate, acetate, fumarate, salicylate, mandelate, andmethanesulphonate.

Suitable pharmaceutically acceptable solvates include hydrates.

The compounds of formula (I) or their salts or solvates are preferablyin pharmaceutically acceptable or substantially pure form. Bypharmaceutically acceptable form is meant, initer alia, of apharmaceutically acceptable level of purity excluding normalpharmaceutical additives such as diluents and carriers, and including nomaterial considered toxic at normal dosage levels.

A substantially pure form will generally contain at least 50% (excludingnormal pharmaceutical additives), preferably 75%, more preferably 90%and still more preferably 95% of the compound of formula (I) or its saltor solvate.

One preferred pharmaceutically acceptable form is the crystalline form,including such form in a pharmaceutical composition. In the case ofsalts and solvates the additional ionic and solvent moieties must alsobe non-toxic.

Unless otherwise stated, “alkyl” groups referred to herein, includingthose forming part of other groups, include straight or branched chainalkyl groups containing up to twelve, suitably up to six carbon atoms.These alkyl groups may be optionally substituted with up to five,suitably up to three, groups selected from the list consisting ofalkoxy, amino, carboxy and esters thereof, cyano, hydroxy, and halogen.

Unless otherwise stated, “alkenyl” and “alkynyl” groups referred toherein include straight and branched chain groups containing from two totwelve, suitably from two to six, carbon atoms. These alkenyl andalkynyl groups may be optionally substituted with up to five, suitablyup to three, groups including those substituents described hereinbeforefor the alkyl groups.

Unless otherwise stated, “cycloalkyl” groups referred to herein includegroups having between three and eight ring carbon atoms. Thesecycloalkyl groups may be optionally substituted with up to five,suitably up to three, groups including those substituents hereinbeforedescribed for the alkyl groups.

Unless otherwise stated, “aryl” includes phenyl, naphthyl, and biphenylgroups, especially phenyl.

Suitable optional substituents for any aryl group include up to five,suitably up to three, groups selected from the list consisting ofalkylnyl, amino, hydroxyalkyl, aminoalkyl, mono-and di-alkylaminoalkyl,alkyl, alkylsulphonylamino, mono- and di-alkylamino, mono- anddi-alkylaminocarbonyl, arylcarbonyl, aralkoxy, arylcarbonylamino,aminocarbonyl, aryl, alkylaminocarbonyl, halo, alkyl, alkenyl, aralkyl,alkoxy, alkoxyalkyl, hydroxy, nitro, amino, cyano, mono- anddi-alkylamino, acyl, acylamino, acyloxy, carboxy and esters thereof,carbamoyl, aryloxy, cycloalkyl, and heterocyclyl.

Unless otherwise stated, “heterocyclyl” and “heterocyclic” suitablyinclude aromatic and non-aromatic, single and fused, rings suitablycontaining up to four heteroatoms in each ring, each of which isselected from oxygen, nitrogen and sulphur. Each ring suitably has from4 to 7, preferably 5 or 6, ring atoms. These heterocyclyl andheterocyclic rings may be unsubstituted or substituted by up to fivesubstituents. A fused heterocyclic ring system may include carbocyclicrings and need include only one heterocyclic ring. Examples includepyridyl, indolinyl, quinolinyl, indolyl, benzoxazolyl, benzothiazolyl,benzothiazolinonyl, and benzoxazolinonyl.

Substituents for any heterocyclyl or heterocyclic group are suitablyselected from cyano, alkyl, aminocarbonyl, nitro, aryl, arylcarbonyl,aryloxy, alkylcarbonyl, halogen, alkyl, aralkyl, alkoxy, hydroxy, amino,carboxy and salts and esters thereof, and aryl.

Unless otherwise stated, the terms “halogen” or “halo” include iodo,bromo, chloro and fluoro; especially chloro, fluoro, and bromo.

Certain of the compounds of formula (I) may contain chiral atoms and/ormultiple bonds, and hence may exist in one or more stereoisomeric forms.The present invention encompasses all of the isomeric forms of thecompounds of formula (I) whether as individual isomers or as mixtures ofisomers, including geometric isomers, tautomers, enantiomers, andracemic modifications.

It has been found that, where a compound of formula (I) exhibits opticalisomerism, one enantiomer possesses a greater affinity for the ORL-1receptor than its antipode.

Accordingly, the present invention also provides an enantiomer of acompound of formula (I) or a derivative thereof.

In a further aspect, the present invention provides a mixture ofenantiomers of a compound of formula (I), or a derivative thereof,wherein one enantiomer is present in a greater proportion than itsantipode.

A further aspect of the invention provides a process for the preparationof a compound of formula (I) wherein R² is hydroxy and R³ is hydrogen,and thereafter, if required, carrying out one or more of the followingoptional steps:

-   (i) converting a compound of formula (I) to another compound of    formula (I);-   (ii) removing any necessary protecting group;-   (iii) preparing an appropriate derivative of the compound so formed;    which process comprises either;    Process A. the reduction of a compound of formula (II)

wherein;

R, R¹, R⁴, and R⁵ are as hereinbefore defined for formula (I) with asuitable reducing agent such as a metal hydride or a borane-containingreducing agent, or;

Process B. reacting a compound of formula (III)

wherein;

R and R¹ are as hereinbefore defined for formula (I) and P represents aprotecting group such as a silyl group, with a compound of formula (I)

wherein;

R⁴ and R⁵ are as hereinbefore defined for formula (I), under reductiveamination conditions such as sodium cyanoborohydride in methanol oracetonitrile (Lane, Synthesis, 135, 1975) and thereafter removing theprotecting group using for example mild acid hydrolysis or a fluorinatedreagent such as tetra-N-butylammonium fluoride to yield the compound offormula (I) wherein R² is hydroxy and R³ is hydrogen. A suitableprotecting group is a silyl group. Procedures for the protection anddeprotection of substituent groups are discussed in Greene and WutsProtective Groups in Organic Synthesis, III Edition, Wiley, New York,(1999).

For a compound of formula (I) wherein R² is hydroxy and R³ is hydrogen,Process A is the preferred process.

For Process A in general, a solution of a compound of formula (II) and asuitable reducing agent in a suitable dry solvent is prepared under asuitable inert atmosphere at a suitable initial temperature and is thenstirred at a suitable reaction temperature for a suitable period oftime. A suitable reducing agent is lithium aluminium hydride, lithiumaluminium hydride/aluminium trichloride, or diisobutylaluminium hydride.A suitable solvent is tetrahydrofuran or diethyl ether. A suitable inertatmosphere is an atmosphere of nitrogen. A suitable initial temperatureis in the range 0–4° C. A suitable reaction temperature is in the range15° C. to the reflux temperature of the solvent. A suitable period oftime is 2–18 hours. The mixture is then quenched, basified, filtered ifnecessary, then, if necessary, extracted into a suitable organicsolvent. The solvent is then removed and the crude product purified.Suitable quenching media are water and saturated aqueous sodiumpotassium tartrate tetrahydrate solution. A suitable base is aqueoussodium hydroxide solution. A suitable organic extraction solvent isdiethyl ether. Conventional methods of cooling and heating such asice/salt baths and electric heating mantles may be employed.Conventional methods of purification such as flash chromatography,trituration, and crystallisation may be employed.

In a preferred aspect of Process A, a solution of aluminium trichloridein dry diethyl ether is added dropwise at 0° C. to a suspension oflithium aluminium hydride in dry diethyl ether under an atmosphere ofnitrogen After stirring for ten minutes, a solution of the compound offormula (II) in dry diethyl ether is added dropwise, the reactionmixture allowed to warm to ambient temperature, and stirred for fourhours. After cooling to 0° C., the reaction is quenched by thesequential addition of water, 15% aqueous sodium hydroxide solution, andwater. The aqueous phase is extracted with diethyl ether, the organicphase is collected, dried with, for example, magnesium sulphate and thesolvent is removed by evaporation. The crude product is purified byflash chromatography followed by trituration.

A compound of formula (II) may be prepared by reaction of a suitablyactivated compound of formula (V)

wherein;R and R¹ as hereinbefore defined for formula (I), with a compound offormula (IV) as hereinbefore defined.

Compounds of formula (V) may suitably be activated prior to reactionwith the compound of formula (V) by formation of the corresponding acylhalide, for example by reaction of the compound of formula (II) with ahalodehydroxylation agent such as oxalyl chloride. Compounds of formula(V) may also be activated in situ i.e. in the presence of the compoundof formula (IV) by the use of activating agents such asdicyclohexylcarbodiimide/1-hydroxybenzotriazole,N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide/1-hydroxybenzotriazole,or O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate.

In general, a compound of formula (II) may be prepared as follows: To asolution of a compound of formula (V) in a suitable dry solvent at asuitable initial temperature under a suitable inert atmosphere is addeda suitable halodehydroxylation agent The solution is warmed to asuitable reaction temperature and for a suitable period of time and thesolvent removed under reduced pressure. A suitable solvent isdichloromethane. A suitable initial temperature is in the range of −2°C. to 4° C. A suitable inert atmosphere is a nitrogen atmosphere. Asuitable halodehydroxylation agent is oxalyl chloride. A suitablereaction temperature is in the range of 15° C. to 25° C. A suitableperiod of time is 12 to 18 hours. Conventional methods of cooling andheating such as ice/salt baths and electric heating mantles may beemployed. The crude acid halide is then reacted with the compound offormula (IV) without further purification in the following manner: At asuitable initial temperature and under a suitable inert atmosphere, asolution of the crude acid halide in a suitable dry solvent is added toa solution of the compound of formula (IV), or a salt thereof, and asuitable hindered base in a suitable dry solvent. A suitable initialtemperature is in the range of −2° C. to 4° C. A suitable inertatmosphere is an atmosphere of nitrogen. A suitable solvent for the acidhalide, and the compound of formula (IV) and the hindered base isdichloromethane. A hindered base is a base which does not act as acompeting nucleophile, such as triethylamine. The reaction mixture isallowed to warm to a suitable reaction temperature for a suitable periodof time, water added, and the organic phase separated, washed with adilute aqueous solution of a suitable mineral acid and dried with, forexample, magnesium sulphate. A suitable reaction temperature is in therange of 15° C. to 25° C. A suitable period of time is 12 to 18 hours. Asuitable mineral acid is hydrochloric acid. The crude compound offormula (II) may be purified by conventional methods of purificationsuch as flash chromatography, crystalisation, and trituration.Conventional methods of cooling and heating such as ice/salt baths andelectric heating mantles may be employed.

In a preferred aspect, the compound of formula (V) is dissolved in drydichloromethane and oxalyl chloride added dropwise at 0° C. under anatmosphere of nitrogen. The solution is allowed to warm to ambienttemperature for about 15 hours and the solvent and excess oxalylchloride removed under reduced pressure. The resulting acid chloride isdissolved in dry dichloromethane, added to a solution of thehydrochloride of the compound of formula (IV) and triethylamine indichloromethane at 0° C. and allowed to warm to ambient temperature forabout 15 hours. Water is then added, the organic phase separated, washedwith 1M aqueous hydrochloric acid and dried with, for example, magnesiumsulphate. The solvent is removed under reduced pressure and the crudecompound of formula (II) purified by flash chromatography.

Compounds of formula (V) may be prepared as described in Bowman,Tetrahedron, 48, 4027, (1992), or Hasegawa, Tetrahedron Lett., 39, 4059,(1998), or may be prepared by transforming the hydroxy group of analcohol of formula (XII) into a suitable leaving group such asmethanesulphonate, p-toluenesulphonate or bromide, and reacting saidcompound with diethyl malonate in presence of a base such as sodiumethoxide to obtain a compound of formula (XOI). The compound of formula(XI) is then alkylated with t-butyl bromoacetate in the presence of abase such as sodium hydride to yield a compound of formula (XIV). Thet-butyl ester is then selectively hydrolysed with, for exampletrifluoroacetic acid to yield the carboxylic acid (XV), which isthereafter converted to the corresponding acyl chloride, cyclised underFriedel-Crafts conditions and subsequently hydrolysed and decarboxylatedusing conventional methods. See Scheme 1.

wherein R and R¹ are as hereinbefore defined for formula (I).

Compounds of formula (IV) may be prepared as described in Elliott,Bioorg. Med. Chem. Lett., 8, 1851, (1998) or may be prepared by reactingan aromatic aldehyde of formula (XVI) with ethyl acetoacetate inpresence of a catalytic amount of an organic base such as piperidine, togive compound (XVII), which is thereafter hydrolysed in basic conditionsfor example in the presence of aqueous sodium hydroxide solution, toyield the carboxylic acid (XVIII), which is then transformed into theimide (XIX) by conversion to its ammonium salt and subsequent pyrolysis,and finally reducing said imide using a suitable metal hydride or aborane-based reagent. See Scheme 2.

wherein R⁴ and R⁵ are as hereinbefore defined for formula (I), or byreacting a carboxylic compound of formula I, wherein P is a suitableprotecting group such as benzyl, with an organometallic compound offormula (KU), wherein M represents a metal such as Li or Mg, for examplearylithium derivatives or Grignard reagents, obtaining an alcohol offormula (XII), dehydrating said alcohol to a compound of formula (XXII)in acidic conditions (e.g. conc. HCl or AcOH/H₂SO₄) and finally reducingand deprotecting the compound of formula (XII) via hydrogenation over asuitable catalyst (e.g. Pd on carbon or PtO₂) or via dissolving metalreduction (e.g. Li or Na in liquid ammonia). See Scheme 3.

wherein R⁴ and R⁵ are as hereinbefore defined for formula (I).

Compounds of formula (W are known, commercially available compounds ormay be prepared according to procedures described in standard referencetexts of synthetic methodology such as J. March, Advanced OrganicChemistry, 3rd Edition (1985), Wiley Interscience.

Compounds of formula (XVI) are known, commercially available compounds,or may be prepared according to procedures described in standardreference texts of synthetic methodology such as J. March, AdvancedOrganic Chemistry, 3rd Edition (1985), Wiley Interscience.

Compounds of formula (XX) are known, commercially available compounds,or may be prepared according to procedures described in standardreference texts of synthetic methodology such as J. March, AdvancedOrganic Chemistry, 3rd Edition (1985), Wiley Interscience.

Compounds of formula (X) are known and may be prepared according toprocedures described in standard reference texts of syntheticmethodology such as J. March, Advanced Organic Chemistry, 3rd Edition(1985), Wiley Interscience.

Compounds of formula (III) may be prepared from compounds of formula(VI)

wherein;

R and R¹ are as hereinbefore defined for formula (I) by protection ofthe hydroxy group with a suitable protecting group such as a silylgroup, followed by reduction of the ester moiety to an aldehyde groupusing a suitable reducing agent such as diisobutylaluminium hydride(Winterfeldt, Synthesis, 617, (1975)).

Compounds of formula (VI) may be prepared from compounds of formula(VII)

wherein;

R and R¹ are as hereinbefore defined for formula (I) by conventionalreduction procedures for example-using a suitable reducing agent such assodium borohydride.

Compounds of formula (VII) may be prepared from compounds of formula (V)by conventional esterification procedures for example those described instandard reference texts of synthetic methodology such as J. March,Advanced Organic Chemistry, 3rd Edition (1985), Wiley Interscience.

In a further aspect, there is provided a process for the preparation ofa compound of formula (I) wherein R² is hydroxy and R³ is C₁₋₆alkyl,which process comprises the oxidation of a compound of formula (a)wherein R² is hydroxy and R³ is hydrogen using a suitable oxidisingagent such as MnO₂, PDC, or DMSO/oxalyl chloride (Swem J. Org. Chem. 432480 (1978)) to give a compound of formula (I′)

wherein;

R, R¹, R⁴, and R⁵ are as hereinbefore defined for formula (I), followedby reaction of the compound of formula (I′) with a suitableorganometallic compound such as an alkylmetal compound for example analkyllithium compound, or a Grignard reagent such as an alkyl Grignardreagent, and thereafter, if required, carrying out one or more of thefollowing optional steps:

-   (i) converting a compound of formula (I) to another compound of    formula (I);-   (ii) removing any necessary protecting group;-   (iii) preparing an appropriate derivative of the compound so formed.

In general, a solution of the compound of formula (I′) in a suitable drysolvent at a suitable initial temperature under a suitable inertatmosphere is added to a solution of the organometallic reagent in asuitable dry solvent. The reaction mixture is stirred at the initialtemperature for a suitable initial time period, then warmed to asuitable second temperature and stirred for a suitable second timeperiod. The mixture is then cooled to the initial temperature andquenched with a suitable quenching medium A suitable solvent for thecompound of formula (I′) and the organometallic reagent is diethylether. A suitable initial temperature is in the range −2° C. to 4° C. Asuitable inert atmosphere is an atmosphere of nitrogen. A suitableinitial time period is 30 minutes to 2 hours. A suitable secondtemperature is 15° C. to 25° C. A suitable second time period is 30minutes to 2 hours. A suitable quenching medium is saturated aqueousammonium chloride solution. The aqueous phase is extracted with asuitable organic solvent such as diethyl ether, the organic extractisolated, dried with for example magnesium sulphate, and the solventremoved under reduced pressure. The crude product is then purified.Conventional means of heating and cooling for example ice/salt baths andelectric-heating mantles may be employed. Conventional methods ofpurification such as flash chromatography, crystallisation, andtrituration may be employed.

In a preferred aspect, a solution of the compound of formula (I′) in drydiethyl ether is added at 0° C. and under an atmosphere of nitrogen to asolution of C₁₋₆alkyl magnesium iodide in dry diethyl ether. The mixtureis stirred at 0° C. for one hour, allowed to warm to ambient temperatureand stirred for a further one hour. The mixture is then cooled to 0° C.and quenched with saturate aqueous ammonium chloride solution. Theaqueous phase was extracted with diethyl ether, the organic layerseparated, dried, and the solvent removed under reduced pressure. Thecrude compound of formula (I) wherein R² is hydroxy and R³ is C₁₋₆alkylis then purified by flash chromatography.

In an additional aspect, there is provided a process for the preparationof a compound of formula (I) wherein R² is amino, C₁₋₆alkylamino, ordi(C₁₋₆alkyl)amino and R³ is hydrogen, which process comprises thereduction of a compound of formula (VIII)

wherein;

R, R¹, R⁴, and R⁵ are as hereinbefore defined for formula (I) and R⁶ andR⁷ are each independently hydrogen or C₁₋₆alkyl, using a suitablereducing agent such as a metal hydride or a borane-based reagent ashereinbefore described in Process A, and thereafter, if required,carrying out one or more of the following optional steps:

-   (i) converting a compound of formula (I) to another compound of    formula (I);-   (ii) removing any necessary protecting group;-   (iii) preparing an appropriate derivative of the compound so formed.

Compounds of formula (VII) may be prepared from compounds of formula(II) as hereinbefore defined by reaction with a compound of formula (IX)HNR⁶R⁷  (IX)wherein;

R⁶ and R⁷ are each independently hydrogen or C₁₋₆alkyl, under reductiveamination conditions as hereinbefore described in Process B.

Compounds of formula (IX) are known, commercially available compounds ormay be prepared according to procedures described in standard referencetexts of synthetic methodology such as J. March, Advanced OrganicChemistry, 3rd Edition (1985), Wiley Interscience.

The above mentioned conversion of a compound of formula (I) into anothercompound of formula (I) includes any conversion which may be effectedusing conventional procedures, but in particular the said conversionsinclude:

-   (a). converting one group R² into another group R².

The above mentioned conversion (a) may be carried out using anyappropriate method under conditions determined by the particular groupschosen.

Suitable conversions of one group R² into another group R², as inconversion (a), include:

-   (i). converting a group R² which represents hydroxy into a group R²    which represents alkoxy; such a conversion may be carried out using    a conventional alkylation procedure, for example treating an    appropriately protected compound of formula (I) with a strong base    such as sodium hydride and alkylating the resultant alkoxide anion    with a suitable alkylating agent such as an alkyl halide, and;-   (ii). converting a group R² which represents hydroxy into a group R²    which represents amino, alkylamino, or dialkylamino; such a    conversion may be carried out using a conventional    dehydroxyamination procedure, for example treating an appropriately    protected compound of formula (I) wherein R² is hydroxy with an    activating agent such as a methanesulphonyl halide or a    p-toluenesulphonyl halide to transform the hydroxy group R² into the    corresponding methanesulphonate or p-toluenesulphonate respectively    and thereafter reacting the activated compound with an amine of    formula (IX) as hereinbefore defined in the presence of a hindered    base such as triethylamine.

As has previously been mentioned, compounds of formula (I) are ligandsof the ORL-1 receptor.

Accordingly, there is provided a compound of formula (I), or apharmaceutically acceptable derivative thereof, as an active therapeuticsubstance.

According to another aspect of the present invention there is provided amethod of modulating the ORL-1 receptor activity in a human or animalpatient in need thereof, which method comprises administering to thehuman or animal patient an effective amount of a compound of formula (I)or a pharmaceutically acceptable derivative thereof.

In a further aspect of the present invention there is provided the useof a compound of formula (I), or a pharmaceutically acceptablederivative thereof, for modulating the ORL-1 receptor activity in ahuman or animal patient.

In yet another aspect of the present invention there is provided the useof a compound of formula (I), or a pharmaceutically acceptablederivative thereof, in the manufacture of a medicament for modulatingthe ORL-1 receptor activity in a human or animal patient.

Said compounds of formula (I) may be agonists or antagonists of theORL-1 receptor.

Accordingly, the present invention provides the use of a compound offormula (I), or a pharmaceutically acceptable derivative thereof, as ananalgesic for the treatment of, for example, acute pain; chronicneuropathic or inflammatory pain including post herpetic neuralgia;neuralgia; diabetic neuropathy and post stroke pain; osteoarthritis/backpain; painful pregnancy labour, and therapy of opioid tolerance anddependence.

Accordingly, the present invention further provides the use of acompound of formula (I), or a pharmaceutically acceptable derivativethereof, in the treatment or prophylaxis of eating disorders such asanorexia and bulimia; anxiety and stress conditions; immune systemdiseases; cardiovascular system dysfunctions; memory loss; cognitivedisorders; motor impairment and neurodegeneration owing to Alzheimer'sdisease; senile dementia; Parkinson's disease or other neurodegenerativepathologies; stroke; epilepsy; altered diuresis and sodium excretion;syndrome of inappropriate secretion of antidiuretic hormone (SLADH);adult respiratory distress syndrome (ARDS); congestive heart failure;cirrhosis with ascites; sexual dysfunctions including impotence andfrigidity; and altered pulmonary function, including chronic obstructivepulmonary disease.

Accordingly, the present invention also provides the use of a compoundof formula (I), or a pharmaceutically acceptable derivative thereof, inthe treatment or prophylaxis of cough; asthma; depression; drug abusesuch as alcohol abuse; dementias such as vascular dementia and AIDSdementia complex; metabolic disorders such as obesity; arterial bloodpressure disorders; and for the control of water balance and sodiumexcretion.

In a further aspect, the present invention provides the use of acompound of formula (I), or a pharmaceutically acceptable derivativethereof, for the manufacture of a medicament as an analgesic for thetreatment of, for example, acute pain; chronic neuropathic orinflammatory pain including post herpetic neuralgia; neuralgia; diabeticneuropathy and post stroke pain; osteoarthritis/back pain; painfulpregnancy labour; and therapy of opioid tolerance and dependence.

In an additional aspect, the present invention provides the use of acompound of formula (I), or a pharmaceutically acceptable derivativethereof, for the manufacture of a medicament for the treatment orprophylaxis of eating disorders such as anorexia and bulimia; anxietyand stress conditions; immune system diseases; cardiovascular systemdysfunctions; memory loss; cognitive disorders; motor impairment andneurodegeneration owing to Alzheimer's disease; senile dementia;Parkinson's disease or other neurodegenerative pathologies; stroke;epilepsy; altered diuresis and sodium excretion; syndrome ofinappropriate secretion of antidiuretic hormone (SIADM); adultrespiratory distress syndrome (ARDS); congestive heart failure;cirrhosis with ascites; sexual dysfunctions including impotence andfrigidity; and altered pulmonary function, including chronic obstructivepulmonary disease.

In yet a further aspect, the present invention provides the use of acompound of formula (I), or a pharmaceutically acceptable derivativethereof, for the manufacture of a medicament for the treatment orprophylaxis of cough; asthma; depression; drug abuse such as alcoholabuse; dementias such as vascular dementia and AIDS dementia complex;metabolic disorders such as obesity; arterial blood pressure disorders;and for the control of water balance and sodium excretion.

Accordingly, in a further aspect, there is provided a method oftreatment of acute pain; chronic neuropathic or inflammatory painincluding post herpetic neuralgia; neuralgia; diabetic neuropathy andpost stroke pain; osteoarthritis back pain; painful pregnancy labour,and therapy of opioid tolerance and dependence, which method comprisesthe administration of a compound of formula (I), or a pharmaceuticallyacceptable derivative thereof, to the mammal in need thereof.

In a further aspect, there is provided a method of treatment orprophylaxis of eating disorders such as anorexia and bulimia; anxietyand stress conditions; immune system diseases; cardiovascular systemdysfunctions; memory loss; cognitive disorders; motor impairment andneurodegeneration owing to Alzheimer's disease; senile dementia;Parkinson's disease or other neurodegenerative pathologies; stroke;epilepsy; altered diuresis and sodium excretion; syndrome ofinappropriate secretion of antidiuretic hormone (SIADH); adultrespiratory distress syndrome (ARDS); congestive heart failure;cirrhosis with ascites; sexual dysfunctions including impotence andfrigidity; and altered pulmonary function, including chronic obstructivepulmonary disease, which method comprises the administration of acompound of formula (I), or a pharmaceutically acceptable derivativethereof, to the mammal in need thereof.

In yet a further aspect, there is provided a method of treatment orprophylaxis of cough; asthma; depression; drug abuse such as alcoholabuse; dementias such as vascular dementia and AIDS dementia complex;metabolic disorders such as obesity; arterial blood pressure disorders;and for the control of water balance and sodium excretion, which methodcomprises the administration of a compound of formula (I), or apharmaceutically acceptable derivative thereof, to the mammal in needthereof.

Administration of a compound in accordance with the invention may be byway of oral, sublingual, transdermal or parenteral administration.

An effective amount of the compound of the invention will depend onfactors such, for example, as the nature and severity of the disorder(s)being treated and on the weight of the mammal. However, a unit does willnormally contain 0.1 to 50 mg, for example 0.5 to 10 mg, of thecompound. Unit doses will normally be administered once or more thanonce a day, for example 2, 3, or 4 times a day, more usually 1 to 3times a day, such that the total daily dose is normally in the range,for a 70 kg adult of 0.1 to 50 mg, for example 0. 1 to 5 mg, that is inthe range of approximately 0.001 to 1 mg/kg/day, more usually 0.005 to0.2 mg/kg/day.

For oral or parenteral administration, it is greatly preferred that thecompound is administered in the form of a unit dose composition, such asa unit dose oral or parenteral composition.

Accordingly, in yet another aspect of the present invention there isalso provided a pharmaceutical composition comprising a compound offormula (I), or a pharmaceutically acceptable derivative thereof, and apharmaceutically acceptable carrier.

Such compositions are prepared by admixture and are suitably adapted fororal or parenteral administration, and as such may be in the form oftablets, capsules, oral preparations, powders, granules, lozenges,reconstitutable powders, injectable and liquid infusible solutions orsuspensions or suppositories.

Tablets and capsules for oral administration are usually presented in aunit dose, and contain conventional excipients such as binding agents,fillers, diluents, tabletting agents, lubricants, disintegrants,colourants, flavourings, and wetting agents. The tablets may be coatedaccording to well known methods in the art.

Suitable fillers include cellulose, mannitol, lactose and other similaragents.

Suitable disintegrants include starch, polyvinylpyrrolidone and starchderivatives such as sodium starch glycolate.

Suitable lubricants include, for example, magnesium stearate.

Suitable pharmaceutically acceptable wetting agents include sodiumlauryl sulphate.

These solid oral compositions may be prepared by conventional methods ofblending, filling or tabletting. Repeated blending operations may beused to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are conventionalin the art.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspensions, solutions, emulsions, syrups, or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example sorbitol,syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats,emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample, almond oil, fractionated coconut oil, oily esters such asesters of glycerine, propylene glycol, or ethyl alcohol; preservatives,for example methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavouring or colouring agents.

Oral formulations also include conventional sustained releaseformulations, such as tablets or granules having an enteric coating.

For parenteral administration, fluid unit dose forms may be preparedcontaining the compound and a sterile vehicle. The compound, dependingon the vehicle and the concentration, can be either suspended ordissolved. Parenteral solutions are normally prepared by dissolving thecompound in a vehicle and filter sterilising before filling into asuitable vial or ampoule and sealing. Advantageously, adjuvants such asa local anaesthetic, preservatives and buffering agents arealso-dissolved in the vehicle. To enhance the stability, the compositionmay be frozen after filling into the vial and the water removed undervacuum.

Parenteral suspensions are prepared in substantially the same mannerexcept that the compound may be suspended in the vehicle instead ofbeing dissolved and sterilised by exposure to ethylene oxide beforesuspending in the sterile vehicle. Advantageously, a surfactant orwetting agent may be included in the composition to facilitate uniformdistribution of the compound of the invention.

As is common practice, the compositions will usually be accompanied bywritten or printed directions for use in the treatment concerned.

Preparation 1

2-Methylphenethyl alcohol methanesulphonate

10 g (0.0734 mol) of 2-methylphenethyl alcohol were dissolved in 200 mLof dry CH₂Cl₂ under a nitrogen atmosphere; the solution was cooled to 5°C., 16.4 mL (0.1175 mol) of triethylamine were added, followed by asolution of 9.1 mL (0.1175 mol) of methanesulphonyl chloride in 100 mLof dry CH₂Cl₂, keeping the temperature below 15° C. The reaction mixturewas allowed to warm to room temperate in 2 h, then 250 mL of water wereadded, the organic phase was collected and the solvent was removed invacuo. The resulting oil was taken up in Et₂O, the organic phase waswashed with 1N HCl and with saturated NaHCO₃ solution, then it was driedand the solvent was removed in vacuo, yielding 14.5 g of the titleproduct which was used without further purification.

IR, ¹H nmr spectra and mass spectra were consistent with the assignedstructure.

Preparation 2

2-(2-o-Tolyl-ethyl)-malonic Acid Diethyl Ester

33.9 mL (0.223 mol) of diethyl malonate were added, under a nitrogenatmosphere and at room temperature, to a solution of sodium ethoxide(prepared in situ by dissolving 2.6 g (0.0151 mol) of Na in 80 mL ofabsolute EtOH). After 30 min, 14.5 g (0.0677 mol) of 2-methylphenethylalcohol methanesulphonate dissolved in 40 mL of abs. EtOH were addeddropwise and the resulting solution was heated to reflux for 3 h. EtOHwas removed in vacuo, the residue was taken up in water and extractedwith Et₂O. The organic phase was washed successively with 10% HCl andbrine, dried and the solvent was removed in vacuo. The excess diethylmalonate was removed by distillation under reduced pressure. Theresulting oil (15.6 g) was used without further purification.

IR, ¹H nmr spectra and mass spectra were consistent with the assignedstructure.

Preparation 3

3,3-Bis-ethoxycarbonyl-5-o-tolyl-pentanoic acid tert-butyl Ester

A solution of 7.7 g (0.0277 mol) of 22-o-tolyl-ethyl)-malonic aciddiethyl ester in 70 ml of dry THF was added dropwise, under a nitrogenatmosphere at room temperature, to a suspension of 1.4 g (0.036 mol) ofNaH (60% dispersion in mineral oil) in 160 mL of dry TH. The reactionmixture was stirred for 30 min, ten 5.3 mL (0.036 mol) of t-butylbromoacetate were added dropwise. After 3 h the reaction mixture wasquenched with water (at 0° C.) and extracted with Et₂O. The organicphase was dried, the solvent was removed in vacuo and the residue waspurified by flash chromatography, eluting with a mixture Hexane/Et₂O8:2, yielding 9.3 g of the title compound.

IR, ¹H nmr spectra and mass spectra were consistent with the assignedstructure.

Preparation 4

3,3-Bis-ethoxycarbonyl-S-o-tolyl-pentanoic Acid

18.7 g (0.0476 mol) of 3,3-bis-ethoxycarbonyl-S-o-tolyl-pentanoic acidtert-butyl ester were dissolved in 40 mL of trifluoroacetic acid andstirred 1 h at room temperature. Trifluoroacetic acid was removed invacuo, the residue was taken up in water and extracted with Et₂O. Theorganic phase was dried and the solvent was removed in vacuo, yielding16.8 g of the title compound which was used without further purification

IR, ¹H nmr spectra and mass spectra were consistent with the assignedstructure.

Preparation 5.

(±)-1-Methyl5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-7carboxylicAcid

16.8 g (0.0499 mol) of 3,3-bis-ethoxycarbonyl-5-o-tolyl-pentanoic acidwere dissolved in 120 mL of CH₂Cl₂ under a nitrogen atmosphere. Thesolution was cooled to 5° C. and 19 mL (0.1498 mol) of oxalyl chloridewere added dropwise. After 3 h the volatiles were removed in vacuo, theresulting oil was dissolved in 200 mL of CH₂Cl₂ and this solution wasadded dropwise, at 0° C. and under inert atmosphere, to a suspension of26.6 g (0.1996 mol) of AlC₃ in 300 mL of CH₂Cl₂. The resultingsuspension was vigorously stirred overnight, during which time it wasallowed to warm to room temperature. Water was added, followed by 1N HClup to pH 1. The layers were separated, the organic phase was dried andthe solvent was removed in vacuo. The resulting crude product was takenup in dioxane (60 mL) and 6N HCl (200 mL) and heated to reflux for 6 h.After cooling, water was added and the reaction mixture was extractedwith Et₂O. The organic phase was dried, the solvent was removed in vacuoand the resulting crude product was purified by flash chromatographyeluting with Et₂O, yielding 5.9 g of compound which was triturated in(i-Pr)₂O, filtered and dried, yielding 4.33 g of the title product.

IR, ¹H nmr spectra and mass spectra were consistent with the assignedstructure.

The following compounds were obtained according to procedures describedin Preparations 1-5:

-   (±)-1,4-Dimethyl-S-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-7-carboxylic    acid;-   (±)-1-Fluoro-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-7-carboxylic    acid, and;-   (±)-1-Bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-7-carboxylic    acid.

IR, ¹H nmr spectra and mass spectra for all the above compounds wereconsistent with the assigned structures.

Preparation 6

(±)-1-Methoxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-7-carboxylicAcid

A suspension of 0.7 g of(±)-1-methoxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-7-carboxylicacid ethyl ester (prepared as described in Bowman, Tetrahedron, 48,4027, 1992) in 2 mL of 2N NaOH was refluxed for 2 h, then cooled andextracted with Et₂O. The aqueous layer was brought to acidic pH with 10%HCl, the precipitate formed was redissolved in Et₂O and the organicphase was washed with water and dried. The solvent was removed in vacuoand the resulting residue was purified by flash chromatography, elutingwith a mixture CH₂Cl₂/MeOH 9:1 respectively, yielding 0.41 g of thetitle compound.

IR and ¹H nmr spectra were consistent with the assigned structure.

Preparation 7

2-(2,6-Dichloro-phenyl)-4-hydroxy-4-methyl-6-oxo-cyclohexane-13-dicarboxylicAcid Diethyl Ester

20 g (114.3 mmol) of 2,6-dichlorobenzaldehyde and 29 mL (228.6 mmol) ofethyl acetoacetate were dissolved in 40 mL of 96% EtOH; 2 mL ofpiperidine were added dropwise and the resulting solution was stirredovernight at room temperature. EtOH was removed in vacuo and theresulting residue was crystallised from Et₂O, obtaining 25.8 g of thetitle product

IR, ¹H nmr spectra and mass spectra were consistent with the assignedstructure.

Preparation 8

3-(2,6-Dichloro-phenyl)-pentanedioic Acid

25.8 g (61.8 mmol) of2-(2,6-chloro-phenyl)₄-hydroxymethyl-6-oxo-cyclohexane-1,3-dicarboxylicacid diethyl ester were dissolved in 200 mL of 96% EtOH, 150 mL of 35%NaOH solution and 60 mL of H₂O; the resulting solution was heated toreflux for 3 h, then the solvent was removed in vacuo and the resultingaqueous solution was carefully acidified at 0° C. with conc. HCl andextracted with AcOEt. The organic solution was dried and the solvent wasremoved in vacuo. The resulting crude solid was triturated with Et₂O,filtered and dried, yielding 14.8 g of the title compound.

IR, ¹H nmr spectra and mass spectra were consistent with the assignedstructure.

Preparation 9

4-(2,6-Dichloro-phenyl)-piperidine-2,6-dione

14.5 g (52 mmol) of 3-(2,6-dichloro-phenyl)-pentanedioic acid weredissolved in 140 mL of conc. NH₄OH solution. All the volatiles wereremoved in vacuo and the resulting solid was heated to 190° C. for 6 h.The crude reaction mixture was taken up in CH₂Cl₂, the organic phase waswashed with 0.1 M Na₂CO₃ solution, dried and evaporated to dryness. Theresulting crude solid was triturate with Et₂O, filtered and dried,yielding 9.37 g of the title compound.

IR, ¹H nmr spectra and mass spectra were consistent with the assignedstructure.

Preparation 10

4-(2,6-Dichloro-phenyl)piperidine hydrochloride

9.0 g (34.9 mmol) of 4-(2,6-dichloro-phenyl)-piperidine-2,6-dione weredissolved in 150 mL of dry THF under a nitrogen atmosphere. Theresulting solution was cooled to 0° C. and 35 mL (ca 350 mmol) ofborane-methylsulphide complex dissolved in 100 mL of dry THF were addeddropwise. The reaction mixture was allowed to warm to room temperature,heated to reflux for 3 h, then cooled to −5° C. and quenched by carefuladdition of 150 mL of 10% HCl solution. The reaction mixture wassubsequently heated to reflux for 3 h, then, after cooling, thevolatiles were removed in vacuo. The residue was taken up in water,basified with 2 N NaOH solution and extracted with AcOEt The organicphase was dried and the solvent was removed in vacuo. The resulting oilwas taken up in CH₂Cl₂, brought to acidic pH with Et₂O/HCl and thesolvent was removed in vacuo. The resulting solid was triturated withEt₂O, filtered and dried, yielding 7.1 g of the title compound.

IR, ¹H nmr spectra and mass spectra were consistent with the assignedstructure.

The following compounds were obtained according to procedures describedin Preparations 7-10:

-   4-(3-Fluoro-2-methyl-phenyl)piperidine hydrochloride;-   4-(2-Chloro-phenyl)piperidine hydrochloride;-   4-Phenyl-piperidine hydrochloride;-   4-(2-Methyl-phenyl)-piperidine hydrochloride;-   4-(2-Fluoro-phenyl)-piperidine hydrochloride;-   4-(3-Methyl-phenyl)-piperidine hydrochloride;-   4-(2,5-Difluoro-phenyl)-piperidine hydrochloride;-   4-(2,6-Difluoro-phenyl)-piperidine hydrochloride;-   4-(2-Chloro-6-fluoro-phenyl)-piperidine hydrochloride;-   4-(2-Bromo-phenyl)-piperidine hydrochloride, and;-   4-(2-Trifluoromethyl-phenyl)-piperidine hydrochloride.

IR, ¹H nmr spectra and mass spectra for all the above compounds wereconsistent with the assigned structures.

Preparation 11

1-Benzyl-4-(3,5-dimethyl-phenyl)piperidin-4-ol

5 mL (36.8 mmol) of 5-bromo-m-xylene were dissolved in 40 mL of dry THFunder a nitrogen atmosphere. The resulting solution was cooled to −50°C. and 36.5 mL (58.4 mmol) of a 1.6 M solution of n-BuLi in hexane wereadded dropwise. The reaction mixture was stirred 30 min, then a solutionof 10.3 mL (58.4 mmol) of 1-benzyl-4-piperidone in 20 mL of dry THF wasadded dropwise; stirring was continued for 1 h at −50° C., then thereaction mixture was allowed to warm to room temperature overnight.Water was added carefully and TIF was removed in vacuo; the resultingaqueous solution was extracted with AcOEt, the organic phase was driedand the solvent was removed in vacuo. The resulting crude product waspurified by flash chromatography, eluting with a mixtureCH₂Cl₂/MeOH/conc. NH₄OH 100:2:0.4 respectively, yielding 5.44 g of thetitle compound.

IR, ¹H nmr spectra and mass spectra were consistent with the assignedstructure.

Preparation 12

1-Benzyl-4-(3-dimethyl-phenyl)-1,2,3,6-tetrahydropyridine

5.44 g (18.41 mmol) of 1-benzyl-4-(3,5-dimethyl-phenyl)-piperidin-4-olwere dissolved in 7 mL of glacial acetic acid, then a mixture of 3.3 mLof glacial acetic acid and S mL of conc. H₂SO₄ was added dropwise,keeping the temperature below 0° C. The reaction mixture was allowed towarm to room temperature and stirred 3 h, then it was poured onto 20 gof crushed ice, carefully basified with conc. NaOH solution andextracted with AcOEt. The organic phase was dried and the solvent wasremoved in vacuo, yielding 4.4 g of the title compound, which was usedwithout further purification.

IR, ¹H nmr spectra and mass spectra were consistent with the assignedstructure.

Preparation 13

4-(3,5-Dimethylphenyl)piperidine

1.24 g of 10% Pd on activated carbon were suspended in 15 mL of water,then a solution of 4.4 g (15.86 mmol) of1-benzyl-4-(3,5-diethylphenyl)-1,2,3,6-tetrahydropyridine in 60 mL ofEtOH was added followed by 1 mL of formic acid The resulting mixture washydrogenated at 45 p.s.i. in a Parr apparatus for 6 h, then the catalystwas filtered off and the solvent was removed in vacuo. The resultingresidue was taken up in water, basified with conc. NH₄OH solution andextracted with CH₂Cl₂. The organic phase was dried and the solvent wasremoved in vacuo, yielding 2.5 g of the title compound, which was usedwithout further purification.

IR, ¹H nmr spectra and mass spectra were consistent with the assignedstructure.

The following compound was obtained according to procedure described inPreparation 13:

4-(2,6-dimethyl-phenyl)-1,2,3,6-tetrahydropyridine.

IR, ¹H nmr spectra and mass spectra for the above compound wereconsistent with the assigned structure.

Preparation 14

4-(2,6-Dimethyl-phenyl)piperidine Hydrochloride

250 mg (35.75 mmol) of lithium wires were added portionwise, under anargon atmosphere at −78° C., to 25 mL of liquid ammonia, then 840 mg(4.47 mmol) of 4-(2,6-dimethylphenyl)-1,2,3,6-tetrahydropyridinedissolved in 15 mL of dry THF were added dropwise. The reaction mixturewas stirred 1 h at −78° C., then it was allowed to warm to roomtemperature. After ammonia has been removed it was cooled to 0° C. and50 mL of water were added. The reaction mixture was extracted withCH₂Cl₂, the organic layer was washed with brine, dried and the solventremoved in vacuo. The resulting oily residue was dissolved in CH₂Cl₂ andbrought to acidic pH with Et₂O/HCl. The solvent was removed in vacuo andthe resulting solid was triturated with (i-Pr)₂O, filtered and dried,yielding 790 mg of the title compound.

IR, ¹H nmr spectra and mass spectra were consistent with the assignedstructure.

Preparation 15

4-(2-Hydroxymethyl-phenyl)-1-piperidinecarboxylic acid,1,1-dimethylethyl Ester

250 mg (0.87 mmol) of4-(2-formyl-phenyl)-1,2,3,6-tetrahydropyridinecarboxylic acid1,1-dimethylethyl ester (prepared as described in Wustrow, Synthesis,993, 1991) were dissolved in 35 mL of absolute EtOH. 125 mg of PtO₂ wereadded and the resulting mixture was hydrogenated in a Parr apparatus at10 p.s.i. for 24 h, then the catalyst was filtered off and the solventwas removed in vacuo, yielding 260 mg of the title compound, which wasused without further purification.

IR, ¹H nmr spectra and mass spectra were consistent with the assignedstructure.

Preparation 16

4-(2-Hydroxymethyl-phenyl)piperidine hydrochloride

260 mg (0.89 mmol) of 4-(2-hydroxymethylphenyl)-1-piperidinecarboxylicacid, 1,1-dimethylethyl ester were dissolved in 20 mL of CH₂Cl₂, 4 mL ofa saturated Et₂O/HCl solution were added and the reaction mixture wasstirred at room temperature for 45 min. The solvent was removed in vacuoand the resulting crude solid was triturated with CH₂Cl₂, filtered anddried, yielding 180 mg of the title compound.

IR, ¹H nmr spectra and mass spectra were consistent with the assignedstructure.

Preparation 17

(±)-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]carbonyl]6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one

1 g (4.58 mmol) of(±)-1-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-7-carboxylicacid was dissolved in 40 mL of dry CH₂Cl₂ and 1.2 mL (13.74 mmol) ofoxalyl chloride were added dropwise at 0° C. under a nitrogenatmosphere. The solution was allowed to warm to room temperatureovernight, then the solvent and the excess oxalyl chloride were removedin vacuo. The resulting acyl chloride was dissolved in 20 mL of dryCH₂Cl₂ and added to a solution of 1.22 g (4.58 mmol) of4-(2,6-dichloro-phenyl)-piperidine hydrochloride and 1.91 mL (13.74mmol) of triethylamine in 30 mL of dry CH₂Cl₂ at 0° C. The reaction mirewas allowed to warm to room temperature overnight, water was added, theorganic phase was collected, washed with 1 N HCl solution and dried. Thesolvent was removed in vacuo and the resulting crude product waspurified by flash chromatography, eluting with a mixture Et2O/Hexane 8:2respectively, yielding 1.4 g of the title compound.

IR, ¹H nmr spectra and mass spectra were consistent with the assignedstructure.

The following compounds were obtained according to procedures describedin Preparation 17:

-   (±)-1-Fluoro-7-[[4-(2-chlorophenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocylohepten-5-one;-   (±)-1-Fluoro-7-[[4-(2-methylphenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocylohepten-5-one;-   (±)-1-Methyl-7-[[42-fluorophenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocylohepten-5-one;-   (±)-1-Methyl-7-[[4-(3-methylphenyl)piperidin-1-ylcarbonyl]-6,7,8,9-tetrahydro-5H-benzocylohepten-5-one;-   (±)-1-Methyl-7-[[4-(2-chlorophenyl)piperidin-1-yl]carbonyl]-0.6,7,8,9-tetrahydro-5H-benzocylohepten-5-one;-   (±)    1-Bromo-7-[[4-(3-methylphenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocylohepten-5-one;-   (±)-1-Bromo-7-[[4-(2-chlorophenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocylohepten-5-one;-   (±)-1-Methyl-7-[[4-(2,5-fluorophenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocylohepten-5-one;-   (±)-1-Methyl-7-[[s(2,6-fluorophenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocylohepten-5-one;-   (±)-1-Methyl-7-[[4-(2-chlorosfluorophenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;-   (±)-1-Methyl-7-[[4-(2-bromophenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocylohepten-5-one;-   (±)-1-Methyl-7-[[4-(2-trifluoromethylphenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;-   (±)-1-Methoxy-7-[(4phenylpiperidin-1-yl)carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;-   (±)-1-Methoxy-7-[[4-(2-methylphenyl)piperidin-1-yl]arbonyl]-6,7,8,9-tetrahydro-5H-benzocylohepten-5-one;-   (±)-1-Methyl-7-[[4-(3-fluoro-2-methylphenyl)piperidin-1)-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;-   (±)-1,4-Dimethyl-7-[[4-(2-methylphenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;-   (±)-1-Methyl-7-[[4-(2,6-dimethylphenyl)piperidin-1-ylcarbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;-   (±)-1-Fluoro-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;-   (±)-1-Fluoro-7-[(4,2,6-dimethylphenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one;-   (±)-1,4-Diethyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5-benzocyclohepten-5-one;-   (±)-1-Methyl-7-[[4-(2,6-dimethylphenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one,    and;-   (±)-1-Methyl-7-[[4-(2-hydroxymethylphenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one.

IR, ¹H nmr spectra and mass spectra for all the above compounds wereconsistent with the assigned structures.

Preparation 18

(±)-1-Hydroxy-([4-(2-methylphenyl)piperidin-1-yilcarbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one

780 mg (1.99 mmol) of(±)-1-methoxy-7-[[4-(2-methylphenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-onedissolved in 15 mL of CH₂Cl₂ were added dropwise, at room temperatureand under a nitrogen atmosphere, to a solution of 1.1 mL (11.94 mmol) ofBBr₃ in 10 mL of CH₂Cl₂. The reaction mixture was stirred 2 h at roomtemperature, then it was poured onto 20 g of crushed ice, basified withconc. NH₄OH and extracted with CH₂Cl₂. The organic layer was dried andthe solvent was removed in vacuo. The resulting crude solid wastriturated with Et₂O, filtered and dried, yielding 600 mg of the titlecompound.

IR, ¹H nmr spectra and mass spectra were consistent with the assignedstructure.

Preparation 19

(±)-1-Trifluoromethanesulfonyloxy-7-[[4-(2-methylphenylpiperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one

600 mg (1.59 mmol) of(+1-hydroxy-7-[[4-(2-methylphenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-onewere dissolved in 5 mL of pyridine under a nitrogen atmosphere and 0.294mL (1.75 mmol) of trifluoromethanesulfonic anhydride were added dropwiseat −5° C. The reaction mixture was allowed to warm to room temperatureafter 5 min and stirred overnight, then it was poured in water,acidified with 20% citric acid solution and extracted with AcOEt Theorganic layer was dried and the solvent was removed in vacuo. Theresulting residue was purified by flash chromatography, eluting withEt₂O, yielding 520 mg of the title compound.

IR, ¹H nmr spectra and mass spectra were consistent with the assignedstructure.

Preparation 20

(±)-1-Vinyl-7-[[4-(2-methylphenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one

510 mg (1 mmol) of(±)-1-trifluoromethanesulfonyloxy-7-[[4-(2-methylphenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-onewere dissolved in 4 mL of DMF under an argon atmosphere, then 72 mg (0.1mmol) of dichlorobis(triphenylphosphine)palladium (II), 340 mg (8 mmol)of LiCl and 105 mg (0.4 mmol) of triphenylphosphine were added, followedby a solution of 0.3 mL (1.04 mmol) of tributyl(vinyl)tin in 0.5 mL ofDMF. The reaction mixture was heated to 100° C. for 6 h, then it waspoured into water and extracted with AcOEt. The organic layer was driedand the solvent was removed in vacuo. The crude reaction mixture waspurified by flash chromatography, eluting with a mixture AcOEt/hexane1:1, yielding 90 mg of the title compound.

IR, ¹H nmr spectra and mass spectra were consistent with the assignedstructure.

The following compound was obtained according to procedure described inPreparation 20:(±)-1-Allyl-7-[[4-(2-methylphenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one.

IR, ¹H nmr spectra and mass spectra for the above compound wereconsistent with the assigned structure.

Preparation 21

(±)-1-Ethyl-7-[[4-(2-methylphenylpiperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol

100 mg of 10% Pd on activated carbon were suspended in 10 mL of water,then a solution of 272 mg (0.7 mmol) of(±)-1-vinyl-7-[[4-(2-methylphenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-onein 50 mL of EtOH was added, followed by 2 mL of formic acid. Theresulting mixture was hydrogenated at 45 p.s.i. in a Parr apparatus for7 h, then the catalyst was filtered off and the solvent was removed invacua. The resulting residue was taken up in CH₂Cl₂ and extracted withwater. The organic phase was dried and the solvent was removed in vacuo,yielding 168 mg of the title compound, which was used without furtherpurification.

IR, ¹H nmr spectra and mass spectra were consistent with the assignedstructure.

Preparation 22.

(±)-1-Methoxy-7-[(phenylpiperidin-1-yl)methyl]-7,8,9-tetrahydro-5H-benzocyclohepten-5one

0.17 mL of the Jones reagent (prepared by mixing 2.67 g of Cr and 2.3 mLof conc. H₂SO₄ and adding water up to a final volume of 10 mL) wereadded to a solution of 0.2 g of(±)-1-methoxy-7-[(4phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-olin 13 mL of acetone. The solution was stirred at room temperature for 1h, then the solvent was removed in vacuo, the residue was taken up inwater, brought to basic pH with 10% NaOH and extracted with CH₂Cl₂. Theorganic phase was dried and the solvent was removed in vacuo, obtaining0.15 g of the title compound, which was used without furtherpurification.

IR and ¹H nmr spectra were consistent with the assigned structure.

EXAMPLE 1

(±)-cis-1-Methyl-7-[142-fluorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-olhydrochloride

380 mg (1 mmol) of(±)-1-methyl-7-[[4-(2-fluorophenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-onedissolved in 5 mL of dry THF were added dropwise, at 0° C. and under anitrogen atmosphere, to 5 mL of a 1 M solution of LiAlH₄ in TBF. Thereaction mixture was allowed to warm to room temperature and then heatedto reflux for 3 h. After cooling to 0° C., the reaction mixture wasquenched by sequential addition of water, 15% NaOH solution and water.After stirring for 1 h, the resulting precipitate was filtered bysuction and the filtrate was evaporated to dryness. The resulting crudeproduct was purified by chromatography, eluting with a mixtureCH₂Cl₂/MeOH/conc. NH₄OH 95:4:0.5 respectively, yielding 60 mg ofcompound which was dissolved in Et₂O and brought to acidic pH withEt₂O/HCl. The solvent was removed in vacuo and the resulting solid wastriturate with acetone, filtered and dried, yielding 58 mg of the titlecompound. m.p.=235–240° C. IR (KBr, cm⁻¹)=3435, 2927, 1492. NMR (freebase, 400 MHz, CDCl₃, δ ppm): 7.43 (d, 1H); 7.29–6.97 (m, 6H); 5.04 (d,1H); 3.13 (dd, 1H); 3.03–2.92 (m, 2H); 2.86 (m, 1H); 2.47 (dd, 1H); 2.33(s, 3H); 2.24 (d, 1H); 2.17–2.00 (m, 6H); 1.85–1.74 (m, 5H); 1.31 (m,1H); 0.88 (m, 1H). MS (m/z): 368 (MH+).

EXAMPLE 2

(±)-1-Methyl-7-[[4-(2-trifluoromethylphenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-oltrifluoroacetate

The title compound was obtained according to the method described inExample 1, but it was purified by flash chromatography on Lichrosolv RP18 stationary phase, by gradient elution with a solvent systemwater/MeCN/TFA 900:100:0.5 respectively and water/MeCN/TFA 100:900:0.5respectively, in a 1:3 relative ratio, yielding 20 mg of the titlecompound

NMR (free base, 400 Mz, CDCl₃, δ ppm): 7.61 (d, 1H); 7.50 (m, 2H); 7.43(d, 1H); 7.28 (m, 1H); 7.14 (dd, 1H); 7.07 (d, 1H); 5.04 (d, 1H); 3.14(dd, 1H); 3.04–2.85 (m, 3H); 2.47 (dd, 1H); 2.33 (s, 3H): 2.30–2.00 (m,7H); 1.89–1.71 (m, 5H); 1.34 (m, 1H); 0.89 (m, 1H). MS (m/z): 418 (MH+).

Compounds of formula (I) and described in Table 1 were obtainedfollowing procedure described in Example 1

TABLE 1 Ex m.p. IR MS No. Name R R¹ R² R³ R⁴ R⁵ (° C.) (cm⁻¹) NMR (400MHz, δ ppm, free base) (m/z) 3 (±)-cis-1-fluoro-7-[[4-(2- F H OH H 2-ClH 245– (KBr); CDCl₃: 7.37–7.09(m, 6H); 6.92(t, 1H); 4.97(d, 1H): 388chlorophenyl) 247 3262, 3.35(dd, 1H); 3.07–2.91(m, 3H); 2.39–2.21(m,2H); (MH+) piperidin-1-yl]methyl]- 2932, 2.20–2.00(m, 6H); 1.88–1.65(m,5H); 1.36(m, 1H); 6,7,8,9-tetrahydro-5H- 1579 0.93(m, 1H).benzocyclohepten-5-ol hydrochloride 4 (±)-1-fluoro-7-[[4-(2- F H OH H2-Me H 231– (KBr); CDCl₃: 7.36(d, 1H); 7.28–7.06(m, 5H); 6.92(t, 1H);367 methylphenyl) 233 3297, 4.97(d, 1H); 3.35(dd, 1H); 3.07–2.92(m, 2H);(M+.); piperidin-1-yl]methyl]- 2927, 2.70(m, 1H); 2.38–2.23(m, 2H);2.34(s, 3H); 2.20– 188; 6,7,8,9-tetrahydro-5H- 1582 1.99(m, 6H);1.87–1.65(m, 5H); 1.37(m, 1H); 117; benzocyclohepten-5-ol 0.93(m, 1H).70 hydrochloride 5 (±)-cis-1-methyl-7-[[4- Me H OH H 3-Me H >250 IR, 1Hnmr spectra and mass spectra were consistent with the assigned(3-methylphenyl) structure. piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H- benzocyclohepten-5-ol hydrochloride 6(±)-cis-1-methyl-7-[[4- Me H OH H 2-Cl H >250 (KBr); CDCl₃: 7.42(d, 1H);7.34(dd, 1H); 7.29(dt, 1H); 383 (2-chlorophenyl) 3411, 7.23(dt, 1H);7.16–7.09(m, 2H); 7.06(d, 1H); (M+.); piperidin-1-yl]methyl]- 2925,5.04(d, 1H); 3.14(dd, 1H); 3.07–2.93(m, 3H); 208 6,7,8,9-tetrahydro-5H-1441 2.47(dd, 1H); 2.33(s, 3H); 2.24(d, 1H); benzocyclohepten-5-ol2.19–2.02(m, 6H); 1.87–1.69(m, 5H); 1.31(m, 1H); hydrochloride 0.88(m,1H). 7 (±)-cis-1-methyl-7-[[4- Me H OH H 2-F 5-F — — CDCl₃: 7.42(d, 1H);7.14(dd, 1H); 7.06(d, 1H); 385 (2,5-difluorophenyl) 6.99–6.90(m, 2H);6.87–6.79(m, 1H); 5.04(d, 1H); (M+.); piperidin-1-yl]methyl]- 3.13(dd,1H); 3.03–2.91(m, 2H); 2.88–2.77(m, 1H); 210 6,7,8,9-tetrahydro-5H-2.46(dd, 1H); 2.32(s, 3H); 2.26–2.00(m, 7H); 1.81– benzocyclohepten-5-ol1.68(m, 5H); 1.38–1.24(m, 1H); 0.87(m, 1H). hydrochloride 8(±)-cis-1-methyl-7-[[4- Me H OH H 2-F 6-F — — CDCl₃: 7.43(d, 1H);7.13(dd, 1H); 7.08(m, 1H); 385 (2,6-difluorophenyl) 7.06(d, 1H); 6.83(d,1H); 6.80(d, 1H); 5.04(d, 1H); (M+.); piperidin-1-yl]methyl]- 3.13(dd,1H); 3.03–2.91(m, 3H); 2.46(dd, 1H); 210 6,7,8,9-tetrahydro-5H- 2.33(s,3H); 2.29–1.97(m, 9H); 1.7 1–1.62(m, 3H); benzocyclohepten-5-ol1.38–1.24(m, 1H); 0.87(m, 1H). hydrochloride 9 (±)-cis-1-vinyl-7-[[4-(2-Vinyl H OH H 2-Me H — — (CDCl₃): 7.53(d, 1H); 7.32(d, 1H); 7.26–7.01(m,376 methylphenyl) 6H); 5.52(dd, 1H); 5.30(dd, 1H); 5.05(d, 1H); (MH+)piperidin-1-yl]methyl]- 4.80(s br, 1H); 3.24(dd, 1H); 2.98(m, 2H);6,7,8,9-tetrahydro-5H- 2.69(m, 1H); 2.49(dd, 1H); 2.34(s, 3H);benzocyclohepten-5-ol 2.28–1.93(m, 6H); 1.85–1.66(m, 5H); 1.33(m, 1H);hydrochloride 0.89(m, 1H). 10 (±)-cis-1-allyl-7-[[4-(2- Allyl H OH H2-Me H — — (CDCl₃): 7.48(d, 1H); 7.25(d, 1H); 7.21–7.04(m, 389methylphenyl) 5H); 5.96(ddt, 1H); 5.03(m, 2H); 4.95(ddt, 1H); (M+.);piperidin-1-yl]methyl]- 3.43(m, 2H); 3.12(dd, 1H); 2.99(m, 2H); 2.69(m,188; 6,7,8,9-tetrahydro-5H- 1H); 2.44(dd, 1H); 2.33(s, 3H); 2.24(d, 1H);2.17– 117 benzocyclohepten-5-ol 1.99(m, 6H); 1.83–1.68(m, 5H); 1.34(m,1H); hydrochloride 0.85(m, 1H). 11 (±)-cis-1-methyl-7-[[4- Me H OH H2-Me 3-F — — (CDCl₃): 7.43(d, 1H); 7.16–7.02(m, 4H); 6.86(dd, 381(3-fluoro-2- 1H); 5.04(d, 1H); 3.13(dd, 1H); 2.99(m, 2H); (M+.);methylphenyl) 2.70(m, 1H); 2.46(dd, 1H); 2.33(s, 3H); 2.26– 206; 70piperidin-1-yl]methyl]- 2.01(m, 7H); 2.23(d, 3H), 1.84–1.68(m, 5H);6,7,8,9-tetrahydro-5H- 1.33(m, 1H); 0.88(m, 1H). benzocyclohepten-5-olhydrochloride 12 (±)-trans-1-ethyl-7-[[4- Et H OH H 2-Me H — — CDCl₃:7.25(d, 2H); 7.19–7.05(m, 5H); 5.03(m, 377 (2-methylphenyl) 1H);3.13–2.87(m, 4H); 2.68(m, 3H), 2.33(s, 3H); (M+.);piperidin-1-yl]methyl]- 2.27–1.97(m, 8H); 1.87–1.69(m, 4H); 1886,7,8,9-tetrahydro-5H- 1.52(m, 2H); 1.17(t, 3H). benzocyclohepten-5-olhydrochloride 13 (±)-trans-1,4-dimethyl- Me 4- OH H 2-Me H — — (CDCl₃,333 K): 7.25(d, 1H); 7.20–7.05(m, 3H); 378 7-[[4-(2-methylphenyl) Me6.98(d, 1H); 6.91(d, 1H); 5.34(t. 1H); 3.20(m, 1H); (MH+)piperidin-1-yl]methyl]- 3.00(m, 2H); 2.78(m, 1H); 2.69(m, 1H); 2.41(s,6,7,8,9-tetrahydro-5H- 3H); 2.32(s, 3H); 2.28(s, 3H); 2.23–1.96(m, 6H);benzocyclohepten-5-ol 1.96–1.54(m, 7H); 1.02(m, 1H). 14(±)-cis-1-methyl-7-[[4- Me H OH H 2-Me 6- — — (CDCl₃): 7.43(d, 1H);7.14(dd, 1H); 7.06(d, 1H); 377 (2,6-dimethylphenyl) Me 6.98(s, 3H), 5,11(s br, 1H); 5.03(d, 1H); 3.13(dd, (M+.); piperidin-1-yl]methyl]- 1H);2.98(m, 3H); 2.46(dd, 1H); 242(s br, 6H); 202 6,7,8,9-tetrahydro-5H-2.33(s, 3H); 2.25(m, 4H); 2.15–1.95(m, 6H); 1.39– benzocyclohepten-5-ol1.15(m, 2H); 0.86(m, 1H). hydrochloride 15 (±)-cis-1-fluoro-7-[[4- F HOH H 2-Me 6- — — (CDCl₃): 7.36(d, 1H); 7.18(m, 1H); 6.97(s, 3H); 382(2,6-dimethylphenyl) Me 6.92(dd, 1H); 4.97(d, 1H); 3.35(dd, 1H); 2.98(m,(MH+) piperidin-1-yl]methyl]- 3H); 2.42(s br, 6H); 2.40–1.97(m, 11H);1.58(m, 6,7,8,9-tetrahydro-5H- 2H); 1.35 (m, 1H); 0.91(m, 1H).benzocyclohepten-5-ol hydrochloride 16 (±)-1,4-dimethyl-7-[[4- Me 4- OHH 2-Me 6- — — (CDCl₃): 6.97(d, 1H); 6.96(s, 3H); 6.92(d, 1H); 392(2,6-dimethylphenyl) Me Me 5.32(t, 1H); 3.19(m, 1H); 3.00–2.89(m, 3H);(MH+) piperidin-1-yl]methyl]- 2.77(m, 1H); 2.42(s br, 9H); 2.42–2.19(m,4H); 6,7,8,9-tetrahydro-5H- 2.28(s, 3H); 2.07(m, 2H); 1.89(m, 1H);1.73(m, benzocyclohepten-5-ol 3H); 1.65–1.53(m, 4H). hydrochloride 17(±)-cis-1-methyl-7-[[4- Me H OH H 2- H — — (CDCl₃): 7.38(d, 1H); 7.30(d,1H); 7.24(d, 1H); 379 (2-hydroxymethyl CH₂OH 7.18(dd, 1H); 7.10(dd, 1H);7.03(dd, 1H); 6.96(d, (M+.); phenyl)piperidin-1- 1H); 4.92(d, 1H);4.64(d, 2H); 3.09–2.83(m, 5H); 204; yl]methyl]-6,7,8,9- 2.76(m, 1H);2.38(dd, 1H); 2.,23(s, 3H); 2.22− 167 tetrahydro-5H- 1.91(m, 7H);1.80–1.61(m, 4H); 1.20(m, 1H); benzocyclohepten-5-ol 0.77(m, 1H).

EXAMPLE 18

(±)-cis-1-Methyl-7-[[(2chloro-6-fluorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-olhydrochloride

3.0 mL of a 1 M solution of diisobutylaluminium hydride in hexane wereadded dropwise, at 0° C. and under a nitrogen atmosphere, to a solutionof 350 mg (0.85 mmol) of(±)-1-methyl-7-[[4-(2-chloro-6-fluorophenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-onein 6 mL of dry THF. The reaction mixture was allowed to warm to roomtemperature overnight, then it was poured onto 20 mL of a saturatedsolution of sodium potassium tartate tetrahydrate; 1 mL of 15% NaOHsolution was added and the aqueous phase was extracted with Et₂O. Theorganic phase was dried and the solvent was removed in vacua. The crudeproduct was purified by flash chromatography, eluting with a mixtureCH₂Cl₂/MeOFconc. NH₄OH 100:4:0.1 respectively, yielding 25 mg ofcompound which was dissolved in Et₂O and brought to acidic pH withEt₂O/HCl. The solvent was removed in vacuo and the resulting solid wastriturate with acetone, filtered and dried, yielding 15 mg of the titlecompound.

NMR (free base, 400 MHz, CDCl₃, δ ppm): 7.43 (d, 1H); 7.16-7.04 (m, 4H);6.93 (ddd, 1H); 5.03 (d, 1H); 3.20–3.10 (m, 2H): 3.02-2.92 (m, 2H); 2.46(dd, 1H): 2.29–1.97 (m, 9H); 1.70–1.62 (m, 3H); 1.32 (m, 1H): 0.86 (m,1H). MS (m/z): 401 (M+.); 226; 210.

EXAMPLE 19

(±)-1-Bromo-7-[[(2-chlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-olTrifluoroacetate

The title compound was obtained according to the method described inExample 18, but it was purified by preparative HPLC on a SupelcosilABZ+plus column, by gradient elution with a solvent systemwater/MeCNITFA 900:100:0.5 respectively (A) and water/MeCN/TFA100:900:0.5 respectively (B), with a gradient from 0% B to 80% (B) in 19min., yielding 14 mg of the title compound.

NMR (free base, 400 MHz, CDCl₃, δ ppm): 7.48 (dd, 1H); 7.367.18 (m, 4H);7.12 (dd, 1H); 7.00 (dd, 1H); 5.03 (m, 1H); 3.35–3.13 (m, 1H); 3.05–2.93(m, 2H); 2.26–2.02 (m, 8H); 1.87–1.70 (m, 6H); 1.58 (m, 1H); 1.26 (m,1H). MS (m/z): 448 (MH+).

Compounds of formula (I) and described in Table 2 were obtainedfollowing procedure described in Example 18

TABLE 2 Ex m.p. IR MS No. Name R R¹ R² R³ R⁴ R⁵ (° C.) (cm⁻¹) NMR (400MHz, δ ppm, free base) (m/z) 20 (±)-trans-1-bromo-7-[[4- Br H OH H 3-MeH >250 (KBr); CDCl₃: 7.47(dd, 1H); 7.23(d, 1H), 7.17(d, 1H); 427(3-methylphenyl) 3326, 7.05–6.97(m, 4H); 5.02(m, 1H); 3.33–3.14(m, 2H);(M+.); piperidin-1-yl]methyl]- 2959, 3.01−2.93(m, 2H); 2.49–2.38(m, 1H);2.33(s, 3H); 188 6,7,8,9-tetrahydro-5H- 1446 2.25–1.92(m, 7H);1.83–1.74(m, 5H); 1.54(m, benzocyclohepten-5-ol 1H); 1.22(m, 1H).hydrochloride 21 (±)-cis-1-methyl-7-[[4-(2- Me H OH H 2-Br H — — CDCl₃:7.53(d, 1H); 7.42(d, 1H); 7.307.24(m, 2H); 428 bromophenyl) 7.13(dd,1H); 7.06(d, 1H); 7.04(m, 1H); 5.04(d, (M+.); piperidin-1-yl]methyl]-1H); 3.13(dd, 1H); 3.05–2.90(m, 3H); 2.47(dd, 1H); 252;6,7,8,9-tetrahydro-5H- 3.33(s, 3H); 2.29–2.01(m, 8H); 1.88–1.64(m, 4H);242; benzocyclohepten-5-ol 1.34(m, 1H); 0.88(m, 1H).

EXAMPLE 22

(±)-cis-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]6,7,8,9-tetrahydro-5H-benzocyclohepten-5-olHydrochloride

A solution of 1076 mg (8.06 mmol) of AlCl₃ in 50 mL of dry Et₂O wasadded dropwise, at 0° C. and under a nitrogen atmosphere, to asuspension of 275 mg (7.25 mmol) of LiAlH₄ in 50 mL of dry Et₂O. Theresulting mixture was stirred for 10 min., then 828 mg (1.92 mmol) of(±)-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]carbonyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-onedissolved in 50 mL of dry Et₂O were added dropwise. The reaction mixturewas allowed to warm to room temperature and stirred 4 h, then it wascooled to 0° C. and quenched with water, 15% NaOH solution and water.The aqueous phase was extracted with Et₂O, the organic phase was driedand the solvent was removed in vacuo. The crude product was purified byflash chromatography, eluting with a mixture CH₂Cl₂/i-PrOH/conc. NH₄OH100:2:0.1 respectively, yielding 200 mg of the cis diastereoisomer asthe faster eluting compound 45 mg of free base were dissolved in CH₂Cl₂,the solution was brought to acidic pH with Et₂O/HCl and the solvent wasremoved in vacuo. The resulting solid was triturated with acetone,filtered and dried, yielding 40 mg of the title compound. m.p.=235–240°C. IR (KBr, cm⁻¹)=3435, 2963, 1436, 1261, 1095. NMR (free base, 400 MHz,CDCl₃, δ ppm): 7.42 (d, 1H); 7.29–7.23 (m, 2H); 7.12 (dd, 1H); 7.05 (d,1H); 7.01 (dd, 1H); 5.03 (d, 1H); 3.52 (tt, 1H); 3.16 (dd, 1H); 3.042.94(m, 2H); 2.74–2.58 (m, 2H); 2.50 (dd, 1H); 2.34 (s, 3H); 2.27 (m, 1H);2.19–2.03 (m, 6H); 1.59–1.40 (m, 31H); 1.32 (m, 1H); 0.90 (m, 1H). MS(m/z): 418 (MH+)

EXAMPLE 23

(±)-trans-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]6,7,8,9-tetrahydro-5H-benzocyclohepten-5ol

The chromatography of the preceding example was continued, obtaining 50mg of the trans diastereoisomer as the slower eluting compound.

NMR (400 MHz, CDCl, δ ppm): 7.30–7.25 (m, 2H); 7.147.00 (m,4H); 5.02 (m,1H): 3.48 (tt, 1H); 3.11–2.87 (m, 4H); 2.71–2.55 (m, 2H); 2.34 (s, 31);2.31–1.99 (m, 8H); 1.51 (m, 3H); 1.17 (m, 1H). MS (m/z): 418 (MH+).

Compounds of formula (I) and described in Table 3 were obtainedfollowing procedure described in Example 22

TABLE 3 Ex m.p. IR MS No. Name R R¹ R² R³ R⁴ R⁵ (° C.) (cm⁻¹) NMR (400MHz, δ ppm, free base) (m/z) 24 (±)-cis-1-fluoro-7-[[4-(2,6- F H OH H2-Cl 6-Cl — — (CDCl₃): 7.36(d, 1H); 7.27(m, 1H); 7.18(m, 1H); 422dichlorophenyl) 7.04(d, 1H); 7.02(d, 1H); 6.92(dd, 1H); (MH+);piperidin-1-yl]methyl]- 4.96(d, 1H); 3.49(tt 1H); 3.35(dd, 1H); 2.98(m,6,7,8,9-tetrahydro-5H- 2H); 2.64(dq, 2H); 2.38–2.00(m, 9H); 1.54(m,benzocyclohepten-5-ol 2H); 1.35(m, 1H); 0.91(m, 1H). hydrochloride 25(±)-1,4-dimethyl-7-[[4-(2,6- Me 4-Me OH H 2-Cl 6-Cl — — (CDCl₃): 7.25(m,2H); 7.02(dd, 1H); 6.98(d, 1H); 432 dichlorophenyl) 6.92(d, 1H);5.33(dd, 1H); 3.47(tt, 1H); 3.18(dd, (MH+) piperidin-1-yl]methyl]- 1H);2.96(m, 2H); 2.78(m, 1H); 2.64(m, 2H); 6,7,8,9-tetrahydro-5H- 2.42(s,3H); 2.42–2.26(m, 4H); 2.28(s, 3H); benzocyclohepten-5-ol 2.17–2.00(m,3H); 1.84–1.47(m, 5H).

Racemic(±)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol(compound of Example 22) was separated by preparative HPLC on chiralstationary phase (Daicel Chiralcel OD, elution with 95:5 Hexane:Ethanol,17 mL/min), obtaining:

EXAMPLE 26

(±)-cis-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol

The title compound was obtained with e.e.>99.8% (HPLC). [α]²⁰ _(D)=−30.7(c=0.5, i-PrOH). ¹H NMR matched that of the racemate.

EXAMPLE 27

(±)-cis-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol

The title compound was obtained with e.e.>99.8% (HPLC). [a]²⁰ _(D)=+32.6(c=0.5, i-PrOH). ¹H NMR matched that of the racemate.

EXAMPLE 28

(±)-1-Methoxy-5methyl-7-[(4-phenylpiperidin-1-yl)methyl]6,7,8,9-tetrahydro-5H-benzocyclohepten-5-olhydrochloride

A solution of 140 mg (0.38 mmol) of(±)-1-methoxy-7-[(4phenylpiperidin-1-yl)methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-onein 5 mL of dry Et₂O was added, at 0° C. and under a nitrogen atmosphere,to 1 mL of a 3 M MeMgl solution in Et₂O. The reaction mixture wasstirred 1 h at 0° C., then allowed to warm to room temperature andstirred an additional hour, then it was cooled to 0° C. and quenchedwith saturated NH₄Cl solution. The aqueous phase was extracted withEt₂O, the organic phase was collected, dried and the solvent was removedin vacuo. The crude product was purified by flash chromatography,eluting with a mixture toluene/MeOH 9:1 respectively, yielding 40 mg offree base, which was dissolved in Et₂O, the solution was brought toacidic pH with Et₂O/HCl and the solvent was removed in vacuo. Theresulting solid was triturated with Et₂O, filtered and dried, yielding30 mg of the title product m.p.=158–160° C.

¹H nmr spectra was consistent with the assigned structure.

Method of Nociceptin Binding Assay

Receptor Cloning and Expression

ORL-1 receptor was stably expressed in a Chinese Hamster Ovary (CHO)cell line (ACC-317) using a pCDN vector. Subclone selection wasperformed by growth in the absence of nucleosides. The cell lineexpressing high numbers of ORL-1 binding sites was selected for furthercharacterization in radioligand binding and signal transduction assay(cAMP and GTPgS assays).

Cell Growth Conditions

CHO cells are grown in suspension, in 1017 SO₃ culture and maintained at37° C. and 5% CO₂. The cells are routinely grown on a shaker in thepresence of 0.05% (v/v) pluronic acid (F68). The maximum cell densityfor this CHO cell lines is 4×106 cells/ml. The cultures are passed twicea week at a 1:5 or 1:10 dilution.

Membrane Preparation by Hypotonic Lysis

All steps are performed at 4° C.

-   1) Harvest cells in PBS (approximately 30×10⁶ cells/tube). Collect    cells by centrifugation (1200 rpm, ca 800×g 5 min).-   2) Resuspend each pellet in 10 mM dibasic phosphate buffer, pH 7.2    (buffer A)-circa 30 ml/pellet. Centrifuge 15000 rpm 10 min (Sorvall    SS-34 rotor).-   3) Resuspend the pellets in the same volume of buffer A, incubate on    ice for 20 min. Centrifuge at 1200 rpm, 5 min and save the    supernatants.-   4) Resuspend the low speed pellets in buffer A again and repeat    step 3) two more times saving the supernatants each time.-   5) Pool the low speed supernatants. Spin (15000 rpm, 10 min) to    collect the membranes.-   6) Resuspend the pellets in buffer A containing 0.32 M sucrose and S    mM EDTA (buffer B). Pool, spin again at high speed to concentrate    the membranes and wash in this storage buffer.-   7) Resuspend in buffer B the final pellet to a final concentration    of 5–10 mg protein/ml (ca 10×10⁶ cells/ml). Freeze the aliquots at    −80° C.    Radioligand Binding

Radioligand binding experiments have been performed in Tris buffer pH7.4 containing 100 ug/ml Bacitracine, 4 ug/ml Leupeptine and 2 ug/mlChymostatine at the final volume of 1 ml, using [³H]-Nociceptin(Amersham, 172 Ci/mmol) as the radioligand.

Binding experiments were carried out at 25° C. for 20 min and thereaction was terminated by filtration through Whatman GF/B filterspretreated with 0.2% PEI. Filters were washed 3 times in Tris buffer pH7.4 at 4° C. The radioactivity present on the discs was measured byliquid scintillation counting using a 2500 Canberra Packard betacounter.

The most potent compounds in accordance with the present invention havean ORL-1 binding affinity (Ki) in the range from 0.1 to 500 nNM.

1. A compound of formula (I)

or a derivative thereof, wherein; R is C₁₋₆alkyl, C₃₋₇cycloalkyl,C₁₋₆alkoxy, hydroxy, halo, C₁₋₆alkenyl, C₁₋₆alkynyl, amino,C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, hydroxyC₁₋₆alkyl,C₁₋₆alkoxyC₁₋₆alkyl, aminoC₁₋₆alkyl, (C₁₋₆alkyl)aminoC₁₋₆alkyl,di(C₁₋₆alkyl)aminoC₁₋₆alkyl; R¹ is hydrogen or R; R² is hydroxy,C₁₋₆alkoxy, amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino; R³ is hydrogen orC₁₋₆alkyl; R⁴ and R⁵ are each independently selected from the listconsisting of perhaloC₁₋₆alkyl, hydrogen, halo, C₁₋₆alkyl, C₁₋₆alkoxy,hydroxy, amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, hydroxyC₁₋₆alkyl,C₁₋₆alkoxyC₁₋₆alkyl, aminoC₁₋₆alkyl, (C₁₋₆alkyl)aminoC₁₋₆alkyl,di(C₁₋₆alkyl)aminoC₁₋₆alkyl, aryl, and COX wherein X may be hydroxy,C₁₋₆ alkoxy, C₁₋₆alkyl, amino, C₁₋₆alkylamino, or di(C₁₋₆alkyl)amino;with the proviso that, when R³ is hydrogen, then R⁴ and R⁵ are not bothhydrogen; and wherein any alkyl group or the alkyl moiety of any groupcontaining such a moiety may be substituted one or more times by halo.2. A compound according to claim 1 wherein R is C₁₋₆alkenyl, C₁₋₆alkyl,halo, or C₁₋₆alkoxy.
 3. A compound according to claim 1 wherein R isvinyl, allyl, ethyl, methyl, fluoro, bromo, or methoxy.
 4. A compoundaccording to claim 1 wherein R is methyl, fluoro, or bromo.
 5. Acompound according to claim 1 wherein R is methyl.
 6. A compoundaccording to claim 1 wherein R¹ is hydrogen or methyl.
 7. A compoundaccording to claim 1 wherein R¹ is hydrogen or 4-methyl.
 8. A compoundaccording to claim 1 wherein R² is hydroxy.
 9. A compound according toclaim 1 wherein R³ is hydrogen or methyl.
 10. A compound according toclaim 1 wherein R³ is hydrogen.
 11. A compound according to claim 1wherein R⁴ is hydroxyC₁₋₆alkyl, halo, perhaloC₁₋₆alkyl, C₁₋₆alkyl, orhydrogen.
 12. A compound according to claim 1 wherein R⁴ ishydroxymethyl, fluoro, trifluoromethyl, chloro, methyl, bromo, orhydrogen.
 13. A compound according to claim 1 wherein R⁴ is2-hydroxymethyl, 2-F, 2-CF₃, 2-Cl, 2-Me, 3-Me, 2-Br, or hydrogen.
 14. Acompound according to claim 1 wherein R⁴ is 2-Cl, 2-F, 2-Me, or 2-Br.15. A compound according to claim 1 wherein R⁴ is 2-Cl or 2-Me.
 16. Acompound according to claim 1 wherein R⁵ is C₁₋₆alkyl, hydrogen, orhalo.
 17. A compound according to claim 1 wherein R⁵ is methyl,hydrogen, fluoro, or chloro.
 18. A compound according to claim 1 whereinR⁵ is hydrogen, 6-Me, 3-F, 5-F, 6-F, or 6-Cl.
 19. A compound accordingto claim 1 wherein R⁵ is hydrogen, 3-F, 6-Me, 6-F, or 6-Cl.
 20. Acompound according to claim 1 wherein R⁵ is 6-Me, 6-F, or 6-Cl.
 21. Anenantiomer of a compound of formula (I) as defined in claim 1 or aderivative thereof.
 22. A mixture of enantiomers of a compound offormula (I) as defined in claim 1, or a derivative thereof, wherein oneenantiomer is present in a greater proportion than its antipode.
 23. Aprocess for the preparation of a compound of formula (I) as defined inclaim 1 wherein R² is hydroxy and R³ is hydrogen, which processcomprises the reduction of a compound of formula (II)

wherein; R, R¹, R⁴, and R⁵ are as hereinbefore defined for formula (I);with a suitable reducing agent such as a metal hydride or aborane-containing reducing agent and thereafter, if required, carryingout one or more of the following optional steps: (i) converting acompound of formula (I) to another compound of formula (I); (ii)removing any necessary protecting group; (iii) preparing an appropriatederivative of the compound so formed.
 24. A process for the preparationof a compound of formula (I) as defined in claim 1 wherein R² is hydroxyand R³ is hydrogen, which process comprises reacting a compound offormula (III)

wherein; R and R¹ are as hereinbefore defined for formula (I) and Prepresents a protecting group; with a compound of formula (IV)

wherein; R⁴ and R⁵ are as hereinbefore defined for formula (I), underreductive amination conditions followed by removal of the protectinggroup and thereafter, if required, carrying out one or more of thefollowing optional steps: (i) converting a compound of formula (I) toanother compound of formula (I); (ii) removing any necessary protectinggroup; (iii) preparing an appropriate derivative of the compound soformed.
 25. A process according to claim 24 wherein the protectinggroup, P, is a silyl group.
 26. A process for the preparation of acompound of formula (I) as defined in claim 1 wherein R² is hydroxy andR³ is C₁₋₆alkyl, which process comprises the oxidation of a compound offormula (I) as defined in claim 1 wherein R² is hydroxy and R³ ishydrogen to give a compound of formula (I′)

wherein; R, R¹, R⁴, and R⁵ are as defined for formula (I) in claim 1,followed by reaction of the compound of formula (I′) with a suitableorganometallic compound and thereafter, if required, carrying out one ormore of the following optional steps: (i) converting a compound offormula (I) to another compound of formula (I); (ii) removing anynecessary protecting group; (iii) preparing an appropriate derivative ofthe compound so formed.
 27. A process for the preparation of a compoundof formula (I) as defined in claim 1 wherein R² is amino,C₁₋₆alkylamino, or di(C₁₋₆alkyl)amino and R³ is hydrogen, which processcomprises the reduction of a compound of formula (VII)

wherein; R, R¹, R⁴, and R⁵ areas defined for formula (I) in claim 1 andR⁶ and R⁷ are each independently hydrogen or C₁₋₆alkyl; and thereafter,if required, carrying out one or more of the following optional steps:(i) converting a compound of formula (I) to another compound of formula(I); (ii) removing any necessary protecting group; (iii) preparing anappropriate derivative of the compound so formed.
 28. A compound offormula (I) as defined in claim 1, or a pharmaceutically acceptablederivative thereof, as an active therapeutic substance.
 29. Apharmaceutical composition comprising a compound of formula (I) asdefined in claim 1, or a pharmaceutically acceptable derivative thereof,and a pharmaceutically acceptable carrier.